OBJECTIVE: The causes and progression of several neurological diseases are influenced by factors that control the stability of neural function. Yet the mechanisms that dictate neural excitation and inhibition are poorly understood. Many studies indicate that homeostatic signaling mechanisms participate in the regulation of neural function, in particular by modulating the strength of synaptic connections. This project aims to clarify the mechanisms of synaptic homeostatic signaling. BACKGROUND/RATIONALE: We published a study demonstrating a role in synaptic homeostasis for an Ephexin signaling system. Ephexin is a Rho-type guanine exchange factor (GEF). Drosophila Ephexin is required presynaptically for synaptic homestasis and localizes in proximity of other components of the nerve terminal. Downstream of Ephexin GEF function, Rho-type GTPases are important for executing homeostatic compensation, in particular Cdc42. Upstream of Ephexin, the Drosophila Eph receptor (Eph) binds Ephexin and Eph mutants have impaired synaptic homeostasis. Components of this signaling system show strong genetic interactions with each other and with CaV2.1 calcium channel mutants. We postulate that this presynaptic signaling system couples homeostatic retrograde signaling at the synaptic plasma membrane to the modulation of presynaptic CaV2.1 function and neurotransmitter release. R00 PHASE DESIGN: Candidate molecules already known in other systems to regulate calcium channel function and Eph/Ephexin/GTP signaling will be tested for roles in synaptic homeostasis. Molecules that do show a role in homeostasis will be placed into the context of our presynaptic signaling system. This work will utilize a combination of approaches for the three-year R00 phase: electrophysiological analysis of synaptic function, genetic mutant analyses, pharmacological inhibition of target molecules, analyses of gene expression and protein localization, transgenic rescue, and genetic epistasis and pathway analyses. TRAINEES: New recruited members of my laboratory will be trained in all aspects of this project. Over the course of three years, this may include a technician, two graduate students, and a postdoctoral fellow.